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KEY POINTS Chance for recovery decreases with increasing length of depressive illness. The first six months of an episode of major depression are an important period in terms of treatment and chance for recovery. The cumulative impact of extended morbidity suggests a progressive course. BACKGROUND 431 subjects with major depression participating in the NIMH Collaborative Depression Study were prospectively observed for five years. These subjects had no history of mania, hypomania, or schizoaffective disorder, as well as no underlying minor depression (at least two years’ duration) and no chronic intermittent depressive disorder. Cumulative recovery probabilities were calculated for intervals ranging from one week to five years. Recovery was defined as remission (Psychiatric Status Rating [PSR] score 1 or 2, equivalent of minimal to absent symptoms, with no significant functional impairment) sustained for at least eight weeks. REFERENCE Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry. 1992;49(10):809-816.

KEY POINTS The hippocampus, a region of the brain involved in conscious memory, may begin to atrophy in depression. The hippocampus is at a “vulnerable intersection” of cognitive, emotional, and neuroendocrine regulation. It is rich in glucocorticoid receptors and is a recipient of significant excitatory glutaminergic innervation. A combined “toxic” impact may precipitate trophic changes. BACKGROUND The MRI scans above were obtained from a healthy control (L) and a person with severe depression (R). Indications of hippocampal atrophy are apparent in the diminished size of the area outlined in red in the enlargement of the scan obtained from the patient with depression. Investigators have found that about half of persons with severe depression exhibit high levels of the stress hormone, cortisol, which is thought to be toxic to neurons. (Source: J. Douglas Bremner, MD, Yale University). REFERENCE Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157(1):115-118.

KEY POINT Patients with depression have abnormalities in cerebral blood flow in specific areas of the brain, implicating them in the cortical circuitry that may play a role in the pathophysiology of depressive symptoms.

KEY POINT There is a reciprocal polysynaptic connection between the ventromedial prefrontal cortex (VMPFC) and the dorsolateral prefrontal cortex (DLPFC) that leads through the cingulate and hippocampus. Increased activity in the DLPFC is often associated with diminished activity of the VMPFC. It is postulated that excessive excitatory (glutaminergic) input from the VMPFC, combined with elevated glucocorticoids, results in hippocampal injury. BACKGROUND Ventromedial PFC: receives integrated sensory information from the orbital PFC as well as fear- and reward-related input from the amygdala, medial temporal lobe, and ventral striatum (nucleus accumbens). It projects to the hippocampus, diencephalon, and brainstem, where it regulates autonomic and neuroendocrine response, pain modulation, aggression, and sexual and eating behaviors.1 Lateral orbital PFC (lateral and posterior): receives highly processed and integrated sensory information from the parietal cortex. It is also connected to the amygdala, ventral striatum, and lateral hypothalamus. Activity is increased in depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and panic disorder. Orbital PFC plays a role in correcting and inhibiting maladaptive, perseverative, and emotional responses (in part, generated by the amygdala).2 Dorsolateral PFC: has been implicated in cognitive control, solving complex tasks, maintenance, and manipulation of information in working memory. Hypoactivity of the DLPFC in depression has been associated with psychomotor retardation and anhedonia.2,3 REFERENCES 1. Öngür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10(3):206-219. 2. Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49:341-361. 3. MacDonald AW III, Cohen JD, Stenger VA, Carter CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science. 2000;288(5472):1835-1838.

KEY POINT The prefrontal cortex and limbic system are organized in intricate networks involved in processing emotional and cognitive information. These areas predominantly utilize GABA and glutamate for neurotransmission. Information processing and mutual relationships are significantly influenced by monoaminergic (5-HT, NE, and DA) projections. BACKGROUND Amygdala: is involved in recruiting and coordinating cortical arousal and neuroendocrine response to underdetermined (surprising and ambiguous) stimuli. The amygdala is also involved in emotional learning and memory. Abnormal activation of the amygdala correlates with degree of depression. (It has also been noted in bipolar depression and anxiety.) The amygdala may be implicated in a tendency to ruminate on emotionally negative memories.1 Hippocampus: has a critical role in episodic, contextual learning, and memory. It is rich in corticosteroid receptors and provides inhibitory feedback to hypothalamic-pituitary-adrenal axis. Hippocampal dysfunction may be responsible for inappropriate context-dependent emotional responses.2 REFERENCES 1. Davidson RJ. Affective neuroscience and psychophysiology: toward a synthesis. Psychophysiology. 2003;40(5):655-665. 2. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol. 2002;53:545-574.

The opening of NMDA glutamate receptors requires the presence of both glutamate and glycine, each of which bind to a different site on the receptor. Magnesium is a negative allosteric modulator (NAM) at NMDA glutamate receptors. When magnesium is also bound and the membrane is not depolarized, it prevents the effects of glutamate and glycine and thus does not allow the ion channel to open. In order for the channel to open, depolarization must remove magnesium while both glutamate and glycine are bound to their sites on the ligand-gated ion channel complex.

AMPA and/or kainate may affect the functioning of NMDA receptors in gating the calcium channel. When glutamate arrives, it binds to the AMPA or kainate receptor, causing the sodium channel to open. This increases the flow of sodium into the neuron and the flow of potassium out of it. This causes the membrane to depolarize; it also triggers a postsynaptic nerve impulse. Depolarization of the membrane removes magnesium from the calcium channel. Coupled with glutamate binding to the NMDA receptor in the presence of glycine, this causes the NMDA receptor to open and allow calcium influx. Calcium influx through NMDA receptors contributes to long-term potentiation, a phenomenon that may be involved in long-term learning, synaptogenesis, and other neuronal functions.

Advances in depression treatment

1.
Matthew Macaluso, D.O.
Assistant Professor and Director of Research
University of Kansas School of Medicine
Medical Director, Via Christi Psychiatric Clinic
Treatment of Major Depression
and Unmet Needs

2.
Potential Conflicts of InterestPotential Conflicts of Interest
 Dr. Macaluso has been principal investigator on clinical trials sponsoredDr. Macaluso has been principal investigator on clinical trials sponsored
by the following entities over the last year:by the following entities over the last year:
 AbbVie (schizophrenia)AbbVie (schizophrenia)
 Eisai (Alzheimer disease)Eisai (Alzheimer disease)
 Envivo (schizophrenia)Envivo (schizophrenia)
 Janssen (treatment resistant depression)Janssen (treatment resistant depression)
 Naurex (treatment resistant depression)Naurex (treatment resistant depression)
 Pfizer (Alzheimer disease)Pfizer (Alzheimer disease)
 All clinical trial and study contracts were with and payments made to theAll clinical trial and study contracts were with and payments made to the
University of Kansas Medical Center Research Institute.University of Kansas Medical Center Research Institute.
2

9.
Treatment Duration:Treatment Duration:
12 weeks at each level at12 weeks at each level at
highest recommended dosehighest recommended dose
1 year follow up after a1 year follow up after a
satisfactory therapeuticsatisfactory therapeutic
responseresponse

16.
Major excitatory neurotranmitter in the brain:Major excitatory neurotranmitter in the brain:
““The Ying to the Yang of GABA”The Ying to the Yang of GABA”
Like GABA, found at 50% of all synapses in theLike GABA, found at 50% of all synapses in the
brain.brain.
Is circuits implicated in the pathophysiology ofIs circuits implicated in the pathophysiology of
major depressionmajor depression
Glutamate as aGlutamate as a
target neurotransmitter systemtarget neurotransmitter system

17.
employed a double-blind, parallel group design in a
small number (n = 30) of patients with treatment
resistant major depression,
used an IV dose of CP-101,606 that did not produce
dissociative symptoms,
evaluated response at prespecified 96 hours after CP-
101,606 administration,
found robust antidepressant response which was
sustained up to 30 days after a single administration.
Antidepressant Effects of the
CP-101,606 (NR2B NMDA Antagonist) versus Placebo

20.
Further replication is needed in a larger scale study.
Development plan should address:
Can an oral drug be developed capable of producing a comparable antidepressant
response?
Is the effect sustained with repeated administration?
If so, how frequently must the drug be administered?
Is efficacy limited to patients with treatment resistant depression?
What is the risk:benefit ratio (i.e., where do such drugs fit within relative to existing
antidepressants)?
Antidepressant Effects of the NR2B NMDA Antagonist,
CP-101,606 versus Placebo